Abstract
Myelin protein zero (P0), a type I transmembrane protein, is the most abundant protein in peripheral nervous system (PNS) myelin—the lipid-rich, periodic structure of membrane pairs that concentrically encloses long axonal segments. Schwann cells, the myelinating glia of the PNS, express P0 throughout their development until the formation of mature myelin. In the intramyelinic compartment, the immunoglobulin-like domain of P0 bridges apposing membranes via homophilic adhesion, forming, as revealed by electron microscopy, the electron-dense, double “intraperiod line” that is split by a narrow, electron-lucent space corresponding to the extracellular space between membrane pairs. The C-terminal tail of P0 adheres apposing membranes together in the narrow cytoplasmic compartment of compact myelin, much like myelin basic protein (MBP). In mouse models, the absence of P0, unlike that of MBP or P2, severely disturbs myelination. Therefore, P0 is the executive molecule of PNS myelin maturation. How and when P0 is trafficked and modified to enable myelin compaction, and how mutations that give rise to incurable peripheral neuropathies alter the function of P0, are currently open questions. The potential mechanisms of P0 function in myelination are discussed, providing a foundation for the understanding of mature myelin development and how it derails in peripheral neuropathies.
Highlights
Myelin is required for axonal saltatory conduction in the central and peripheral nervous systems (CNS and PNS, respectively) of vertebrates [1]
The basal expression of P0 before the onset of myelination raises doubts about the apparent redundancy of P2 and myelin basic protein (MBP) [47], especially since MBP is an essential membrane stacker in CNS myelin [17], and both MBP and P2 are required for the long-term stability and the correct ultrastructure formation of PNS myelin [46,48]. These questions will serve as the major focus of this short review, which aims to motivate further studies in the field—especially those that are not dependent on simplified model systems—in order to establish a complete model of P0 and its role as an executive factor of PNS myelination
P0 is the Executive PNS Membrane Stacker In PNS myelin, P0 is responsible for the formation of the intraperiod line (IPL)—the 5-nm narrow intramyelinic compartment, where apposing Ig-like domains adhere to one another, bringing the two myelin membranes together [42,77,78]
Summary
Myelin is required for axonal saltatory conduction in the central and peripheral nervous systems (CNS and PNS, respectively) of vertebrates [1]. Compact myelin must remain stable to ensure myelin-facilitated insulation; mutations that compromise the structure or function of myelin proteins, or autoimmunogenic events that involve these proteins may result in crippling incurable diseases that involve demyelination—the systematic destruction of myelin and its insulative ultrastructure These conditions include peripheral neuropathies in the PNS, such as Charcot–Marie–Tooth disease (CMT) and Dejerine–Sottas syndrome (DSS) [29,30], and multiple sclerosis in the CNS [31]. These questions will serve as the major focus of this short review, which aims to motivate further studies in the field—especially those that are not dependent on simplified model systems—in order to establish a complete model of P0 and its role as an executive factor of PNS myelination
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